- Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor
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Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) withthe bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold Cmax and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere spacer unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.
- Stepan, Antonia F.,Subramanyam, Chakrapani,Efremov, Ivan V.,Dutra, Jason K.,O'Sullivan, Theresa J.,Dirico, Kenneth J.,McDonald, W. Scott,Won, Annie,Dorff, Peter H.,Nolan, Charles E.,Becker, Stacey L.,Pustilnik, Leslie R.,Riddell, David R.,Kauffman, Gregory W.,Kormos, Bethany L.,Zhang, Liming,Lu, Yasong,Capetta, Steven H.,Green, Michael E.,Karki, Kapil,Sibley, Evelyn,Atchison, Kevin P.,Hallgren, Andrew J.,Oborski, Christine E.,Robshaw, Ashley E.,Sneed, Blossom,O'Donnell, Christopher J.
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experimental part
p. 3414 - 3424
(2012/06/01)
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- NOVEL ALPHA-(N-SULFONAMIDO)ACETAMIDE COMPOUNDS INCORPORATING DEUTERIUM AS INHIBITORS OF BETA AMYLOID PEPTIDE PRODUCTION
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The present disclosure provides novel deuterated alpha-(N-sulfonamido)acetamide compounds, their pharmaceutical composition, processes thereof and a method for the treatment of Alzheimer's disease, head trauma, traumatic brain injury, and/or dementia pugilistica and/or other conditions associated with β-amyloid peptide.
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Page/Page column 13
(2010/10/03)
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- Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor
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During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aβ40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aβ40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.
- Gillman, Kevin W.,Starrett Jr., John E.,Parker, Michael F.,Xie, Kai,Bronson, Joanne J.,Marcin, Lawrence R.,McElhone, Kate E.,Bergstrom, Carl P.,Mate, Robert A.,Williams, Richard,Meredith, Jere E.,Burton, Catherine R.,Barten, Donna M.,Toyn, Jeremy H.,Roberts, Susan B.,Lentz, Kimberley A.,Houston, John G.,Zaczek, Robert,Albright, Charles F.,Decicco, Carl P.,MacOr, John E.,Olson, Richard E.
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scheme or table
p. 120 - 124
(2010/12/20)
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- Novel Alpha-(N-Sulfonamido)Acetamide Compound as an Inhibitor of Beta Amyloid Peptide Production
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The present invention provides a novel alpha-(N-sulfonamido)acetamide compound, its pharmaceutical composition, processes thereof and a method for the treatment of Alzheimer's disease and other conditions associated with β-amyloid peptide.
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Page/Page column 22
(2009/05/28)
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